FUNCTIONAL ANALYSIS OF POLYCYSTIN IN DROSOPHILA

果蝇多囊素的功能分析

• 批准号: 6344806
• 负责人: XIANGYI LU
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344806
• 关键词: Drosophilidae; biological signal transduction; chromosome deletion; expression cloning; gene interaction; gene mutation; genetic library; genetic models; genetic promoter element; in situ hybridization; laboratory mouse; membrane proteins; model design /development; phenotype; polycystic kidney

Description: (Taken directly from the application) Polycystic kidney disease (PKD) is a multigene disorder characterized by the growth of fluid-filled cysts, mainly in the kidney. Mutations in at least three genes, PKD1, PKD2 and PKD3, may give rise to the autosomal dominant form of PKD (ADPKD). Evidence suggests that the etiology of cyst initiation associated with PKD1 mutations results from two separate gene inactivation events. The first is an inherited mutation in one PKD1 allele; the second mutation arises in the normal allele during kidney development or maturation. We will test this "second hit" hypothesis as a mechanism for the onset of polycystic kidney disease by producing mice containing both a primary mutation in Pkd1 and a conditional second-hit mutation that can be induced somatically in the other murine Pkd1 allele. These mice will be analyzed for phenotypes associated with ADPKD. Additionally, the combination of mutations will test the Pkd1 missense mutation (Project 3) in a more physiologically relevant model. Finally, the long-range goal of this project is to generate an animal model in which the development of renal, hepatic and other pathophysiology associated with polycystic kidney disease can be analyzed and understood and in which modes of treatment can be tested.

描述：（直接从应用中取）多囊性肾脏疾病（PKD）是一种多基因疾病，其特征是充满液体的囊肿，主要是在肾脏中。至少三个基因PKD1，PKD2和PKD3中的突变可能引起PKD（ADPKD）的常染色体显性形式。有证据表明，与PKD1突变相关的囊肿起始病因来自两个单独的基因失活事件。第一个是一个PKD1等位基因中的遗传突变。第二突变是在肾脏发育或成熟期间正常等位基因出现的。我们将通过产生含有PKD1初级突变的小鼠和有条件的第二击突变，可以在其他鼠PKD1等位基因中诱导，这是多囊性肾脏疾病发作的一种机制。这些小鼠将分析与ADPKD相关的表型。此外，突变的组合将在更相关的模型中测试PKD1错义突变（项目3）。最后，该项目的远程目标是生成动物模型，在该模型中，可以分析和理解与多囊性肾脏疾病相关的肾脏，肝和其他病理生理学的发展，并可以测试治疗模式。